The clinical investigation of fully human monoclonal antibodies against the costimulatory molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) has demonstrated durable benefit for a subset of patients with metastatic melanoma. These clinical investigations have also provided important insight into mechanisms of effective anti-tumor immune responses that have provided new opportunities for cancer treatments. We have discovered that CTLA-4 blockade with ipilimumab can induce profound immune mediated destruction of the vasculature feeding tumor deposits in post-treatment biopsies. While this emphasizes the critical importance of angiogenesis to tumor growth, it also infers an ability of the immune system to recognize and effectively destroy tumor vasculature in a selective manner. The clinical efficacy of targeting vascular endothelial growth factor (VEGF) and its effect on tumor angiogenesis has been extensively studied in clinical trials with the use of the anti-VEGF antibody bevacizumab. VEGF also possesses potent immune suppressive function on antigen presenting cells. As a result, potential synergic effects on the tumor vasculature exist when combining the targeting of VEGF with immune modulation through CTLA-4 blockade. Given our observations of the profound effects on tumor vasculature in melanoma patients receiving ipilimumab and the known effects of bevacizumab, we propose a phase I study testing the combination of these agents in patients with metastatic melanoma. PUBLIC HEALTH RELEVANCE: Improved understanding of mechanisms of immune function has recently provided novel ways to take the brakes off the immune system to treat cancer. One such means has been to block the molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), an innate inhibitory signal to the immune system. Preliminary evidence for blocking CTLA-4 in patients has shown that this can be accomplished to effectively treat melanoma. Interestingly, part of the anti-tumor response involves an immune attack of the blood vessels feeding the tumors. In addition, the major factor known to be involved in the formation of blood vessels that feed tumors, vascular endothelial growth factor (VEGF), has also been found to suppress the immune system. An antibody that blocks VEGF has been shown to be highly effective when combined with other treatments such as chemotherapy against many types of cancer. We propose to combine for the first time an antibody that blocks CTLA-4 to take the brakes off the immune system with an antibody that blocks VEGF to block blood vessel formation to tumors. Importantly we seek to understand synergies in combining these two drugs that together could target the blood vessels feeding melanoma deposits.